NM_000018.2(ACADVL):c.1182+1G>A AND Very long chain acyl-CoA dehydrogenase deficiency

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jun 28, 2018)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000001689.5

Allele description [Variation Report for NM_000018.2(ACADVL):c.1182+1G>A]

NM_000018.2(ACADVL):c.1182+1G>A

Gene:
ACADVL:acyl-CoA dehydrogenase very long chain [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17p13.1
Genomic location:
Preferred name:
NM_000018.2(ACADVL):c.1182+1G>A
HGVS:
  • NC_000017.11:g.7223238G>A
  • NG_007975.1:g.8405G>A
  • NM_000018.2:c.1182+1G>A
  • NM_000018.3:c.1078_1182del105
  • NM_001033859.1:c.1116+1G>A
  • NC_000017.10:g.7126557G>A
  • NM_000018.3:c.1182+1G>A
Note:
A mutation on the splice site of exon 11 causes skipping of exon 11 in the ACADVL mRNA product.
Nucleotide change:
IVS11DS, G-A, +1
Links:
OMIM: 609575.0002; dbSNP: rs113690956
NCBI 1000 Genomes Browser:
rs113690956
Observations:
1

Condition(s)

Name:
Very long chain acyl-CoA dehydrogenase deficiency (VLCAD)
Synonyms:
Long chain acyl-CoA dehydrogenase deficiency
Identifiers:
MedGen: C3887523; Orphanet: 26793; OMIM: 201475

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000021845OMIMno assertion criteria providedPathogenic
(Nov 7, 1995)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV000220283Counsylcriteria provided, single submitter
Likely pathogenic
(Apr 29, 2014)
unknownliterature only

PubMed (2)
[See all records that cite these PMIDs]

Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015),

Citation Link,

SCV000225143EGL Genetic Diagnostics,Eurofins Clinical Diagnosticscriteria provided, single submitter
Pathogenic
(Oct 24, 2013)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV000654919Invitaecriteria provided, single submitter
Pathogenic
(Jun 28, 2018)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknown1not providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function.

Van Goor F, Yu H, Burton B, Hoffman BJ.

J Cyst Fibros. 2014 Jan;13(1):29-36. doi: 10.1016/j.jcf.2013.06.008. Epub 2013 Jul 23.

PubMed [citation]
PMID:
23891399

Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database.

Pena LD, van Calcar SC, Hansen J, Edick MJ, Walsh Vockley C, Leslie N, Cameron C, Mohsen AW, Berry SA, Arnold GL, Vockley J; IBEMC..

Mol Genet Metab. 2016 Aug;118(4):272-81. doi: 10.1016/j.ymgme.2016.05.007. Epub 2016 May 13.

PubMed [citation]
PMID:
27209629
PMCID:
PMC4970910
See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000021845.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In a patient with VLCAD deficiency (201475) associated with infantile cardiomyopathy and sudden death, Strauss et al. (1995) identified a homozygous G-to-A transition in the consensus dinucleotide of the donor splice site in intron 11 of the ACADVL gene, resulting in the skipping of exon 11.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Counsyl, SCV000220283.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From EGL Genetic Diagnostics,Eurofins Clinical Diagnostics, SCV000225143.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not providednot providednot provided

From Invitae, SCV000654919.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change affects a donor splice site in intron 11 of the ACADVL gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs113690956, ExAC 0.002%). This variant has been reported as homozygous or in combination with other ACADVL variants in individuals affected with VLCAD deficiency (PMID: 7479827, 27209629). This variant is also known as IVS11+1 in the literature. ClinVar contains an entry for this variant (Variation ID: 1622). Experimental analyses of fibroblasts from an affected individual homozygous for this variant showed that it causes the in-frame skipping of exon 11 and results in a loss of VLCAD protein expression (PMID: 7479827). In addition, another individual heterozygous of this variant showed 50% residual VLCAD enzyme activity in lymphocytes (PMID: 21932095). In summary, this variant is a rare splice site change which has been reported in affected individuals with evidence of disrupting RNA splicing and protein function. For these reasons, it has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 17, 2019

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